Subcutaneous hormone pellets



United States Patent SUBCUTANEOUS HORMONE PELLETS Hermann Klette, Frankfurt am Main, Germany, assignor to Erich M. H. Radde, New York, NY.

No Drawing. Original application October 20, 1950, Se-

rial No. 193,042, now Patent No. 2,824,546, dated February 25, 1958. Divided and this application February 25, 1958, Serial No. 717,303

Claims priority, application Germany November 2, 1949 6 Claims. (Cl. 167-'58) This invention relates to a new and valuable hormone preparation and more particularly to a hormone preparation having an initially strong and a subsequently prolonged activity, and to a process of making same.

The present application is a division of my copending application Serial No. 193,042, filed October 30, 1950, now Patent No. 2,824,546, and entitled Treating Animals With Hormone Preparation.

It is one object of the present invention to provide a preparation containing, as active ingredient, a water insoluble hormone, said preparation exerting an initially strong and a subsequently prolonged hormone activity which preparation is especially adapted for implantation in human and veterinary therapy.

Another object of the present invention is to provide a simple and effective process of producing such a hormone preparation.

Other objects of the present invention and advantageous features thereof will become apparent as the description proceeds.

It is known to use in veterinary as well as human therapy solutions of steroid and the like water insoluble hormones in vegetable oils or in the form of pellets which are implanted. But these methods of application have a number of disadvantages. Solutions of the hormones in oil are very quickly absorbed. Hence, their effect lasts only for a comparatively short time. In order to obtain a more lasting effect, the injection has to be repeated quite frequently. Implantation of pellets on the other hand requires skilled personnel and is usually done by the physician him'self. Although they exert a prolonged effect, one has no way to determine the exact duration of said effect. Quite often the implanted pellets become covered with connective tissue by which they are, so to say, encysted. Such encapsulation results in their losing their effectiveness completely, because the hormone cannot, be dissolved and absorbed from such encapsulated cysts by the body fluids. Sometimes they are even eliminated by the body under suppuration. Furthermore, the initial effect of said implanted pellets is only very slight and sometimes insufficient to produce the desired therapeutic or other result. Aqueous suspensions of hormones have also been suggested, but the effect of the known suspensions is also rather uncertain.

. It has been found, however, that uniform, certain and prolonged effects are achieved when applying preparations of a composition according to this invention.

In principle, a preparation according to the. present invention which exerts a strong initial and subsequently a prolonged hormone effect consists in preparing pellets, tablets, small cylinders, pills and other structures which can be implanted easily into the body, with hormone particles of different particle size and/or different absorbability. Such pellets and the like are composed, for insize crystals, for instance, of crystals of more than 0.01

mm. diameter, while their outer layers covering the core I partly or completely, consist of particles of a size less than 0.01 mm. diameter or of crystals which are readily binding agent soluble in the body fluids, and a core is formed from such particles around which a coating consisting of finer hormone particles moistened likewise with a concentrated solution of a binding agent which is readily soluble in the body fluids, is placed in a suitable manner. The outer layer may consist of a water-soluble hormone with a suitable binding agent. As binding agents there may be used cellulose ether compounds such as methyl cellulose and others, gum acacia, sugar syrup, blood serum, agar, tragacanth, and the like. After drying the resulting two part pellets under suitable conditions a pellet is obtained which on implantation will first release very rapidly the hormone in the outer layer due to the large surface of the small particles or the solubility in body fluids of the water-soluble hormone, thus, causing an initial shock-like effect, while the-core, due to the larger particle size of the hormone present therein, will be absorbed more slowly, thus, effecting a more prolonged action. In principle, the composition of a bipartite pellet according to the present invention must be such, that, after implanting the same, it will be capable to separate into a crystal mixture consisting of discrete particles of different size and, hence, of different absorbability by the body. Implants of this type do not possess the disadvantages of the known implants which consist of a solid, coherent mass of the hormone in question, because shortly I Preparations according to the present invention are preferably produced with the'natural follicle hormones such as estradiol, estrone, estriol, and their derivatives, especially their esters, such as estradiol benzoate, estradiol dipropionate and the like and with synthetic compounds having the activity of such estrogenic hormones, for instance, compounds of the stilbene series, such as diethyl stilbestrol, di-(p-hydroxyphenyl) hexadiene, di-(p-hydroxyphenyl) hexane and their derivatives, especially their esters, but also compounds such as ethinyl estradiol, doisynolic acid, equilenic acid and the like, di-(p-methoxyphenyl) phenyl ethylenebromide and others more. Di-.

(p-rnethoxyphenyl) hexadiene has proved of special value I because, on account of its specific crystal structure, it is capable of forming especially suitable preparations.

Although compounds having the activity of the natural follicle hormones 'are especially suitable for this purpose, 1 other hormones may also be used, such as the corpus luteum hormones progesterone and ethinyl testosterone: the male sex hormones testosterone and methyl testostame and their derivatives, especially their esters, such as testosterone propionate and the like, the adrenocon tical hormones, such as desoxycorticosterone and its acetate, corticosterone, cortisone, and other ll-substituted compounds of this type such as prednisone, prednisolone and the like. In general, this invention is applicable to all steroid hormones. and their synthetic analogues of which an initial shock effect and, at the same time, a prolonged effect on application is desired.

An especially suitable field of application of the prep arations according to this invention is the veterinary field. It is known that, when fattening female animals,

'Patented July 21, 1959 I factthat-the-sexual functions are only gradually reduced: wherebyfinally-so-called selflcastration-takes place the reasonafor which is, among others, luteinisation and fatty degeneration of the ovaries. With male animals the sexual instinct disturbs also the fattening effect and diminishes the quality of their meat. Therefore, they usually are subjected to bloody castration in order to achieve full fattening effect.

In all these cases the applicationof preparations of compounds having the activityof estrogenic hormones according to the present invention has proved to be of great advantage. But it was -.found that for effecting complete and hormonal castration in the male as well as the female animal, definite minimum amounts of the hormonal substance have to be applied to the animal,

part of which must be very rapidly absorbable so as to cause a shock-like effect while the remainder must be absorbed gradually, i.e. in a prolonged manner. Under these circumstances hormonal castration takes place already after a much shorter starting period, namely after a period of 3 to 4 weeks at the most, while when applying the previously used amounts of hormones said changing period was much longer and was about 7 to. 10 weeks.

Furthermore, it has been found that with said minimum effective doses a modification in the metabolism of the treated animals takes place causing fattening, said fattening etfect being directly proportional to the amount of hormone applied. Gains in weight are obtained thereby which are 50-100% higher than with control animals kept under the same conditions. Due to the prolonged eifect of the hormone preparation according to this invention, the state of castration and of fattening is maintained with female animals for any length of time and with male animals for about four months. Besides the extraordinary fattening result, the meat quality is improved because its structure becomes less dense and fat is interspersed therein, and it acquires a lighter color. The disadvantage of the meat of male animals, especially that of boars, having a disagreeable specific odor and taste so that it is unfit for human consumption, is almost completely eliminated by the treatment 4 Animal I.U.lkg. live weight Bulls 20,000. Cows, oxen, heiiers 18,000. B 65,000. Bloody castrated boars, sow 60,000. R s 20,000. Sheep 15,000. Goats, male 25,000. Goats, female 18,000. 01d cocks and hens 600,000 I.U./animal. Geese, turkeys 700,000 I.U./animal.

The following examples serve to illustrate the inven-' tion without, however,.limiting the same thereto.

Example 1 A paste-like mixture containing only very little water is made by moistening estradiol benzoate crystals having a particle, sizeof about 0.1-0.3 'mmhdiametenwitha.

concentrated aqueous solution'of gumacacia whereby the amount of binding agent is just high enough to cause of about 0.0010.005 mm..diameter with a concentrated aqueous solution of methyl cellulose.

The pastes are then fed into an extrusion machine,

the head of which is provided with two orifices, onein themiddle forming a core and the other concentrically surrounding the former, thus,'. forming a tube which, on

account of the adhesiveness of the paste sticks to the.

inner core and forms a cover around it. The mass con taining the coarse estradiolbenzoate crystals if forced through the inner orifice while the mass containing the fine estradiol crystals is forced through the outer concentrically arranged orifice. The extruded strand is then quickly dried and cut into pieces, which contain the desired amount-of hormone in each piece, thus, forming pellets and the like according to the present invention.

The diameter of the implant is preferably about 2 mm.

of which 1.2 mm.-is formed by the core while the ring surrounding said core has a thickness of 0.4 mm.

Example 2 A tablet of 1.5 mm. diameter and 1.5 mm. height is pressed from di-(p-acetoxyphenyl) hexadiene crystals.

having a particle size of about 0.2-0.3 mm. diameter and a suitable binding agent, such as the sodium salt of carboxy methyl cellulose, whereby care is taken that the pressure is not too high but that the crystals substantially maintain their size and shape and are not reduced in size to powder. This tablet is then used as a core around which in a manner known per se a coating is applied consisting of a concentrated sugar-syrup containing di-(pacetoxyphenyl) hexadiene crystals having a particle size of about 0.001-0005 mm. diameter. Thereby pellets are obtained consisting of a core of coarse crystals and a coating of fine crystals which pellets can be implanted.

quite easily.

Example 3 Crystals of cortisone of a particle size of about 0.2- 0.3 mm. in diameter are moistened with a 2% gelatin solution and the moist mixture is formed into pills. Care is taken that the crystals substantially retain their original particle size and crystal structure. The pills are then covered with a sugar-coating containing crystals of cortisone of a particle size of about 0.001 mm. to 0.005 mm. in diameter in such a manner that the proportion of the core of large crystals to the coating of small crystals is about :100. The resulting pellets are especially suitable for implantation in the treatment of rheumatoid arthritis. intra-articular injection.

of course, similar preparations having an inner core 1 of large size crystals and an outer core of small size crystals or of water soluble hormones other than estro genie and adrenocortical hormones may also be used. Suitable local anesthetics that do not irritate the body and do not react with or affect the properties of the active hormone ingredients may also be added. It is also pos-' sible to produce pellets of such hormones which contain the crystals of different particle size mixed with each other although the pellets consisting of a core of large I crystal particles and a coating of small crystal particles crystals of hormoneshaving the activity of steroid hor- They may also be used with advantage for mones, the particle size of said crystals being substantially lower than 0.01 mm. and a binding agent, said hormone preparation disintegrating under the influence of the body fiuids into said hormone particles of difierent particle size.

2. A solid shaped hormone preparation suitable for implantation comprising an inner core containing crystals of hormones having the activity of steroid hormones, the particle size of said crystals substantially exceeding 0.01 mm. and an outer coating containing crystals of hormones having the activity of steroid hormones, the particle size of said crystals being substantially lower than 0.01 mm., said hormone preparation disintegrating under the influence of the body fluids into said hormone particles of different particle size.

3. The solid shaped hormone preparation according to claim 2, wherein the hormone having the activity of steroid hormones is an estrogenic hormone.

4. The solid shaped hormone preparation according to claim 2, wherein the hormone having the activity of steroid hormones is di-(p acetoxy phenyl) hexadiene.

References Cited in the file of this patent UNITED STATES PATENTS Kirchmeyer Apr. 10, 1956 Klette Feb. 25, 1958 OTHER REFERENCES Kendall: Adreno Cortex Conf., 1949, Pp. and 46. 

1. A SOLID SHAPED HORMONE PREPARATION SUITABLE FOR IMPLANTATION COMPRISING CRYSTALS OF HORMONED HAVING THE ACTIVE OF STEROID HORMONES, THE PARTICLE SIZE OF SAID CRYSTALS SUBSTANTIALLY EXCEEDING 0.01 MM. AND SMALL CRYSTALS OF HORMONES HAVING THE ACTIVITY OF STEROID HORMONES, THE PARTICLES SIZE OF SAID CRYSTALS BEING SUBSTANTIALLY LOWER THAN 0.01 MM. AND A BINDING AGENT, SAID HORMONE PREPARATION DISINTEGRATING UNDER THE INFLUENCE OF THE BODY FLUIDS INTO SAID HORMONE PARTICLES OF DIFFERENT PARTIOLE SIZE. 